EVIDENCE FOR A 1,2-HYDRIDE SHIFT IN THE MICROSOMAL METABOLISM OF THE HETEROCYCLE L-158,338, A NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONIST

L-158,338 is an imidazo[4,5-b]pyridine derivative that is a potent and highly selective angiotensin II receptor antagonist. Rat liver micros omal metabolism of [C6-H-3]L-158,338 gave a major metabolite that was monohydroxylated at the C6 position of the imidazo-pyridine but showed partial retention of the radiolabel. This biotransformation necessita ted a shift of the radiolabel from the C6 position to another site wit hin the molecule. We have investigated the mechanism of this biotransf ormation using H-3-, H-3/C-14-, and H-2-labeled L-158,338. Metabolites were identified by FAB/MS, LC/MS, and H-1-NMR. Results of these studi es show that the microsomal metabolism of L-158,338 to its C6-monohydr oxylated derivative was mediated by a 1,2 hydride shift.